title: FGF14 regulates the intrinsic excitability of cerebellar Purkinje neurons.
abstract: A missense mutation in the fibroblast growth factor 14 (FGF14) gene underlies SCA27, an autosomal dominant spinocerebellar ataxia in humans. Mice with a targeted disruption of the Fgf14 locus (Fgf14(-/-)) develop ataxia resembling human SCA27. We tested the hypothesis that loss of FGF14 affects the firing properties of Purkinje neurons, which play an important role in motor control and coordination. Current clamp recordings from Purkinje neurons in cerebellar slices revealed attenuated spontaneous firing in Fgf14(-/-) neurons. Unlike in the wild type animals, more than 80% of Fgf14(-/-) Purkinje neurons were quiescent and failed to fire repetitively in response to depolarizing current injections. Immunohistochemical examination revealed reduced expression of Nav1.6 protein in Fgf14(-/-) Purkinje neurons. Together, these observations suggest that FGF14 is required for normal Nav1.6 expression in Purkinje neurons, and that the loss of FGF14 impairs spontaneous and repetitive firing in Purkinje neurons by altering the expression of Nav1.6 channels.
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Vikram G
authors.initials: VG
authors.lastname: Shakkottai
authors.forename: Maolei
authors.initials: M
authors.lastname: Xiao
authors.forename: Lin
authors.initials: L
authors.lastname: Xu
authors.forename: Michael
authors.initials: M
authors.lastname: Wong
authors.forename: Jeanne M
authors.initials: JM
authors.lastname: Nerbonne
authors.forename: David M
authors.initials: DM
authors.lastname: Ornitz
authors.forename: Kelvin A
authors.initials: KA
authors.lastname: Yamada
mesh_terms: D000200:Action Potentials; D000818:Animals; D002531:Cerebellum / Q000502:physiology; D019706:Excitatory Postsynaptic Potentials; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011689:Purkinje Cells / Q000502:physiology*; D015222:Sodium Channels / Q000378:metabolism
chemical_list: D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C491046:Scn8a protein, mouse; D015222:Sodium Channels; C112971:fibroblast growth factor 14; D005346:Fibroblast Growth Factors